The space of Mall confirmed in humans: A response to “Portal venous branches as an anatomic railroad for a gut-bile duct axis”
Authors: Iris E.M. de Jong, Neil D. Theise, Rebecca G. Wells
Journal: Journal of Hepatology (2023)

Portal venous branches as an anatomic railroad for a gut-bile duct-axisJournal of HepatologyVol. 79Issue 2PreviewAffecting primarily the large extrahepatic bile ducts, primary sclerosing cholangitis (PSC) is a chronic, inflammatory, and fibro-obliterative cholangiopathy with an unknown trigger.1 In PSC, concomitant inflammatory bowel disease (IBD) is prevalent, with ulcerative colitis (UC) diagnosed in the majority of such cases. However, UC in patients with PSC differs from classical UC2 with (i) a predominantly right-sided and often mild-to-moderate colitis, (ii) a significantly higher risk for colon cancer in the ascending colon, and (iii) different responses to pharmacological therapies. Full-Text PDF We read with great interest the recent Letter to the Editor from Fickert and Lin et al. wherein they describe studies in search of an entero-biliary connection to explain disease processes in ulcerative colitis (UC) and primary sclerosing cholangitis (PSC).[1]Fickert P. Lin A.C. Ritschl H. Hammer N Denk H. Portal venous branches as an anatomic railroad for a gut-bile duct-axis.J Hepatol. 2023; 79: e82-e84Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar They injected the portal veins and hepatic arteries with blue- and red-colored acrylic, respectively, and demonstrated the existence of a connection between branches of the portal vein entering the liver and vessels traveling through the interstitial spaces of the large bile ducts. Importantly, the authors found such a connection in the healthy livers of both mice and humans. As they note, this finding has important implications as a potential explanation for the clinical link between UC and PSC, suggesting an anatomic route for inflammatory signals from the gut to reach the bile ducts via the portal vein and biliary interstitial spaces and then trigger an inflammatory response. We suggest an additional perspective: that this work is the human extension of groundbreaking studies from the great American anatomist Franklin P. Mall, who used a similar injection approach in cat livers to identify a perilobular space – now known as the "space of Mall" – connecting the portal vein and portal tract reticular tissues (Fig. 1).[2]Mall F.P. A study of the structural unit of the liver.Am J Anat. 1906; V: 227-308Crossref Scopus (136) Google Scholar Mall found that after an injection of Prussian-blue gelatin into the portal vein, a "zone of blue" appeared in the portal unit, especially in the larger portal tracts where the connective tissue is more extensive. He concluded that: "The blue extravasates from the capillaries at the center of the portal unit and invades the connective tissue to reach the beginning of the lymphatics, when of course it is carried rapidly from the liver"(2). Mall's studies demonstrated that materials flowing into the liver through the hepatic artery and the portal vein find their way to mixing in the pre-lymphatic, interstitial spaces within the portal tract stroma. Of relevance to the studies of Fickert and Lin et al., our own recent work suggests that the adventitial spaces surrounding portal veins are also continuous with the peribiliary interstitial spaces and thus are an additional, parallel channel between the gut and liver.[3]Cenaj O. Allison D.H.R. Imam R. Zeck B. Drohan L.M. Chiriboga L. et al.Evidence for continuity of interstitial spaces across tissue and organ boundaries in humans.Commun Biol. 2021; 4: 436Crossref PubMed Scopus (23) Google Scholar We congratulate the authors on their beautiful work, which extends the early efforts of Mall to human and rodent livers. These findings, in both cases from healthy livers, add to our understanding of PSC pathogenesis by demonstrating a channel in healthy livers that connects the gut and liver/biliary tree via the vasculature, and could serve as a conduit for inflammatory cells and signals (recognized by cholangiocytes, bile duct-associated macrophages, or other immune cells) that contribute to PSC. Notably, Fickert and Lin et al. also demonstrate the continued importance of anatomical studies and the relevance of even centuries-old work to modern scientific discovery. We look forward to further details as the authors investigate their hypothesis further, in particular as they explore possible relationships between the portal vein and small vs. large ducts in the pathogenesis of PSC. The authors did not receive any financial support to produce this manuscript. The authors of this study declare that they do not have any conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. IEMdJ created Fig. 1B. All authors discussed the manuscript concept, participated in writing and editing all drafts of the manuscript, and approved the final version. The following are the supplementary data to this article: Download .pdf (.22 MB) Help with pdf files Multimedia component 1